Natural killer (NK) cells kill virus-infected and tumor target cells without prior sensitization. Each NK cell expresses a multitude of activating and inhibitory receptors, and the interplay of signals determines the outcome of NK cell activity. NK cell-mediated cytolysis of target cell involves polarized degranulation at effector-target interface. Peripheral blood NK cell constitutes about 10% of lymphocytes, and approximately 90% of peripheral blood NK cells are CD56(dim)CD16(+); however, there is a distinct subset of NK cells, CD56(bright)CD16(-), expressed by certain lymphoid organs which are able to produce large amounts of cytokines including interferon-γ, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor, but the cytotoxicity is attained only on their prolonged activation. In this review, we discuss the accumulated data on distinct phenotypes of NK cells in human uterus, liver, intestine, skin, and lung and also attempt to correlate their phenotype with corresponding activity and functions, with significant stress on the role of NK cells in pathology in the specific organs. Our detailed understanding of altered NK cell activity in different organs and their inherent cytotoxic activity against tumor target cells will help us design better immunotherapeutic strategies in NK cell-mediated cancer therapies.